Identificazioni di nuove alterazioni genetiche nell'adenocarcinoma duttale pancreatico e nelle lesioni pre cancerose mediante tecnologia Whole Genome Sequencing e Oncoscan Array

PDA is the fourth leading cause of cancer death, with a 5-years survival rate of 5% . Surgery remains the most effective treatment, but only 20% of patients are suitable for radical resection. Advances in chemotherapy, represented by FOLFIRINOX and by gemcitabine plus nab-paclitaxel regimens, have resulted in a modest outcome improvement..A thorough understanding of the genetic changes that will drive pancreatic carcinogenesis can lead to identification of biomarkers for early detection and targets for therapy. We used an approach with high resolution cytogenetic analysis Oncoscan Array and WES a bioinformatic, clinically-oriented interpretation of data to understand what are the most relevant pathways altered in precursor lesions and overt cancers to identify new therapeutic options for patients affected by PDA. In this study a total of 20 formalin fixed paraffin embedded samples from IPMN, profiled by Oncoscan and were analysed 30 fresh-frozen biopsies by WES . We identified in IPMN multiple copy number alterations and interestingly, differences were seen in the lesions at different stages, with 7 IPMN with low-intermediate dysplasia carrying a nearly normal karyotype and 13 IPMN with complex Karyotype (> 4 alterations), showing high grade dysplasia. A specific gain of chromosome arm 3q was found in IPMN with complex Karyotype (92%). This gain of 3q is particularly interesting for the presence of oncogenes such as PIK3CA, GATA2 and TERC that are part of pathways that deregulate cell growth and promote disease progression. In 30 sample analyzed with WES our results confirmed the high prevalence of KRAS, CDKN2A, TP53 and SMAD4 mutations. In particular, 93.7% of tumor samples exhibited somatic mutations acti¬vating KRAS and gene amplifications .The identification of these markers at an early stage of disease onset helps to identify patients at risk for cancer progression and new candidates for a more specific targeted therapy